4-tertiary amino-lower alkylamino-quinoline carboxamides and carboxylates



United States Patent 3,362,954 4-TERTIARY AMINO-LOWER ALKYLAMINO-QUINOLINE CARBOXAMIDES AND CAR- BOXYLATES Alexander R. Surrey, Albany,N.Y., assignor to Sterling Drug Inc., New York, N.Y., a corporation ofDelaware No Drawing. Filed Aug. 9, 1966, Ser. No. 571,199 Claimspriority, application Great Britain, Aug. 12, 1965, 34,644/ 65 21Claims. (Cl. 260-247.2)

This invention relates to compositions of matter of the class of4-tertiary-aminoalkylamino-quinolines.

This application is a continuation-in-part of my 00- pending applicationSer. No. 392,642, filed Aug. 27, 1964, now abandoned.

The invention resides in the concept of a composition having a molecularstructure in which the quinoline nucleus has attached thereto in the4-position a lowertertiary-amino-(lower-alkyl) amino radical and in the3- or 2-position a N-[(lower-tertiary-amino)(lower-alkyl)] carbamyl orlower-carbalkoxy radical.

Thus, there are provided the compounds of Formula I where Y and Y areeach lower-alkylene having two to six carbon atoms and having itsconnecting linkages on diflerent carbon atoms, and, NB and NB are eachlowertertiary-amino selected from the group consisting of di-(lower-alkyl) amino, N- (lower-alkyl) N- (lower-hydroxyalkyD-amino,piperidino, (lower-alkylated)-piperidino, pyrrolidino,(lower-alkylated)pyrrolidino and morpholino. 'Ihe CONH--Y' group isattached to either the 2- or 3-position of the quinoline ring. Thebenzenoid ring of Formula I can be substituted by low-molecular weightsubstituents, e.g., halo, lower-alkyl, lower-alkoxy,lower-alkylmercapto, lower-alkanoylamino, lower-alkylamino, nitro,amino, hydroxy, lower-alkanoyloxy, benzyloxy, tn'halomethyl, and thelike, at any of the available positions, i.e., 5, 6, 7 or 8, and wheremore than one substituent is present, they can be the same or differentand they can be in any of the various position combinations relative toeach other. Such additions to the molecular structure of the inventiveconcept herein described are, therefore, equivalents of the subjectmatter sought to be patented.

The compounds of Formula I are useful because of their anti-inflammatoryproperties as established by known pharmacological test procedures,e.g., inhibition of granuloma pouch formation in rats, inhibition ofdextraninduced local foot endema in rats, and inhibition ofendotoxin-induced lung inflammation in mice.

The term halo, as used hereinabove, means c-hloro, bromo, iodo orfluoro.

Unles otherwise indicated, the adjective lower, as used herein,designates a group having from one to six carbon atoms, e.g.,lower-alkyl means alkyl radicals having from one to six carbon atoms andis illustrated by methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,2-butyl, n-amyl, isoamyl, n-hexyl, 3-hexyl, and the like.

The term lower-alkylene, as used herein and designated as Y and Y inFormula 1, means alkylene radicals having from two to six carbon atomsand having its two free valence bonds, i.e., connecting linkages, ondifierent carbon atoms and is illustrated by CH CH 3;:62354 PatentedJan. 9, 1968 I CHzCHzCHCHa, CHzCHCHrCHaCH;

CHzJHCHaCHrOHaCHa --CH CH CH CH CH CH and the like. Also, thelower-alkylene radicals Y and Y of Formula I can be interrupted by O orS, e.g.,

CH CH OCH CH CH CH CH CH SCH CH CH etc., or substituted by hydroxy,e.g.,

CH CH (OH) CH etc.

The compounds of Formula I where Y and Y are NB=NB' are prepared byheating a lower-alkyl 4-chloroquinoline-3(or 2)-carboxylate (II) with atleast two molar equivalents of the appropriate tertiary-aminoalkylamineIII), illustrated structurally as follows:

C OOR HzNY-NB II III IIIH-Y-N B C O N H-Y-N B where R is lower-alkyl,preferably ethyl or methyl, and Y and NB have the meanings designatedabove. The reaction is run by heating the reactants in phenol at aboutC. for a heating period of about fifteen to twenty hours.

The compounds of Formula I Where Y and Y are different and/ or NB and NBare different are prepared by heating a lower alkyl 4 (tertiaryaminoalkylamino)- quinoline-3 (or 2)-carboxylate (IV) with a molarequivalent of the appropriate tertiary-aminoalkylamine (Illa),illustrated as follows:

IV Illa where R is lower-alkyl, preferably ethyl or methyl, Y, Y, NB andNB have the meanings given above for Formula I. The reaction is runusing the reaction conditions 3 given above for the preparation of thecompound of Formula Ia.

The intermediates of Formula IV constitute another aspect of myinvention. They are prepared as follows:

COOR

where X is halo, preferably chloro or iodo, and R, Y and NB have themeanings already given. The reaction conditions can be varied, asillustrated in the specific examples below.

Further to being useful as intermediates, compounds of Formula IV areuseful because of their anti-inflammatory properties as established byknown pharmacological test procedures illustrated hereinabove and, also,because of their wound healing properties as established by theirability on oral administration to accelerate the normal rate of skinwound healing and burn healing in rats. Particularly preferredembodiments because of their wound healing properties are thelower-alkyl 4-[5-.(lower-tertiary-amino) 2-pentylamino]3-quinolinecarboxylates, e.g., ethyl7-chloro-4-(S-diethylamino-Z-pentylamino)-3-quinolinecarboxylate, ethyl7-chloro-4 [S-(N- ethyl-N-2-hydroxyethylamin0)2-pentylamino1-3-quinolinecarboxylate, or salts thereof.

The compounds of Formulas I, Ia and IV are useful both in free base formand in acid-addition salt form and both forms are within the purview ofthe invention, and are considered to be one and the same invention. Theacid-addition salts are simply a usually more convenient form for use;and, in practice, use of the salt form inherently amounts to use of thebase form. The acids which can be used to prepare the acid-additionsalts are preferably those which produce, when combined with the freebase, pharmacodynamically acceptable salts, that is, salts wh se anionsare relatively innocuous to the animal organism in pharmacodynamic dosesof the salts, so that the beneficial properties inherent in the freebase are not vitiated by side effects ascribable to the anions; in otherwords, the latter do not substantially affect the pharmacodynamicproperties inherent in the cations. In practicing my invention, I foundit convenient to employ the hydrochloride salt. However, otherappropriate pharmacodynamically acceptable salts within the scope of theinvention are those derived from mineral acids such as hydrobromicacid,'hydriodic acid, nitric acid, phosphoric acid, sulfamic acid, andsulfuric acid; and organic acids such as acetic acid, citric acid,tartaric acid, lactic acid, methanesulfonic acid, ethanesulfonic acid,quinic acid, and the like, giving the hydrobromide, hydriodide, nitrate,phosphate, sulfa mate, sulfate, acetate, citrate, tartrate, lactate,methanesulfonate, ethanesulfonate and quinate, respectively.

The acid-addition salts are prepared preferably by reacting the freebase and acid in an organic solvent, e.g., ethanol, in which case thesalt separates directly or can be obtained by concentration of thesolution.

Although pharmacodynamically acceptable salts are preferred, allacid-addition salts are within the scope of my invention. Allacid-addition salts are useful as sources of the fi'ee base form even ifthe particular salt per se is not desired as the final product, as forexample when the salt is formed for purposes of purification oridentification, or when it is used as an intermediate in pretwoquaternary nitrogen atoms of the compounds of Formula IV, i.e., thenitrogen atoms of NB and/or the quinoline n'ng. These salts are usefulfor further identification of the aforesaid compounds. The quaternaryammonium salts are obtained by the addition of esters having a molecularweight less than about 200 to the free base form of the compounds. Apreferred class of esters comprises lower-alkyl, lower-alkenyl havingthree to six carbon atoms or benzyl esters of inorganic acids or organicsulfonic acids of the formula Z-An' where Z is loweralkyl, lower-alkenylhaving three to six carbon atoms or benzyl and An is defined as Anabove. Z when benzyl can be substituted in the benzene ring by from oneto three substituents illustrated by, but not limited to loweralkyl,lower-alkoxy, halo, nitro, lower-alkylamino, lower alkylmercapto, andthe like. Z-An is thus illustrated by, but not limited to methylchloride, methyl bromide, methyl iodide, ethyl bromide, propyl chloride,2-hydroxyethyl bromide, allyl chloride, allyl bromide, methyl sulfate,methyl benzenesulfonate, methyl p-toluenesulfonate,

' benzyl chloride, benzyl bromide, p-chlorobenzyl chloride,

p-nitrobenzyl chloride, o-chlorobenzyl chloride, 3,4-dichlorobenzylchloride, p-methoxybenzyl chloride, and the like. The quaternaryammonium salts are prepared by mixing the free base and the lower-alkyl,lower-alkenyl or benzyl esters in an organic solvent inert under theconditions of reaction, for example, ethanol, methanol, ether,acetonitrile and the like, or alternatively, in the absence of asolvent. Heating is preferably used to facilitate the reaction, althoughquaternary formation takes place at room temperature but a longerreaction time is needed. The quaternary ammonium salt separates directlyor can be obtained by concentration of the solution.

The molecular structures of the compounds of my invention areestablished by their mode of synthesis and corroborated by thecorrespondence of calculated and found values for the elementaryanalyses and by infrared (IR) spectral analyses.

The following examples will further illustrate the invention without,however, limiting it thereto.

EXAMPLE 1 N (2-diethylaminoethyl) 4 (2diethylaminoethylamino)-3-quinolinecarboxamide-a mixture containing 54g. of ethyl 4-chloro-3-quinolinecarboxylate, 54 g. of 2diethylarm'noethylamine and 54 g. of phenol was heated with stirring at130 C. for twenty hours and then poured into two liters of water. Theresulting precipitate was solubilized by addition of concentratedhydrochloric acid. The resulting solution was extracted with chloroformto remove the phenol; the solution was then made weakly basic byaddition of 35% aqueous sodium hydroxide solution and extracted withchloroform to remove any un: reacted ethyl4-chloro-3-quinolinecarboxylate; the solution was then made stronglybasic with 35% aqueous'sodium hydroxide solution and extracted firstwith chloroform and then with ethylene dichloride. The extracts of thestrongly basic solution were combined, washed with water, dried overanhydrous potassium carbonate and;

. 113.8 C. (corn);

Analysis.-Calcd. for C22H35'N5O: c 68.61; H, 9.16.

Found: C, 68.36; H, 9 :18. v

EXAMPLE 2 N (2 diethylaminoethyl) 7 chloro 4 (2diethylaminoethylamino)-2-quinolinecarboxamide was prepared followingthe procedure described in Example 1 using 14.5 g. of ethyl4,7-dichloro-2-quinolinecarboxylate, 17.5 g. ofZ-diethylaminoethylamine, 14.5 g. of phenol, a heating period oftwenty-four hours at 130 C., and using ethylene dichloride as theextracting solvent. There was thus obtained 20 g. of the product,N-(Z-diethylaminoethyl) 7 chloro 4 (2 diethylaminoethylamino) 2-quinolinecarboxamide, which was taken up in 100 ml. of isopropylalcohol. To the solution was added 25 ml. of 6 N solution of hydrogenchloride in ethanol, ether was added to near tubidity, and the solutionallowed to stand. The solid that separated was collected, recrystallizedfrom isopropyl alcohol, dried in a vacuum oven at 100 C. for three daysto yield 4 g. of N-(2-diethylaminoethyl)-7- chloro 4 (2diethylaminoethylamino) 2 quinolinecarboxamide as its trihydrochloride,M.P. 265.6267.2 C. (corn) with decomposition.

Analysis.Calcd. for C H ClN O-3HCl: Cl, 20.22; N, 13.20. Found: Cl",19.76; N, 13.11.

EXAMPLE 3 N (2 diethylaminoethyl) 7 chloro 4 (2diethylaminoethylamino)-3-quinolinecarboxamide was prepared followingthe procedure described in Example 1 using 8.0 g. of ethyl4,7-dichloro-3-quinolinecarboxylate, 7.0 g. of Z-diethylaminoethylamine,8.0 g. of phenol and a heating period of twenty hours at 130 C. Therewas thus obtained 2.6 g. of N-(Z-diethylaminoethyl)-7-chloro- 4 (2diethylaminoethylamino) 3 quinolinecarboxamide, M.P. 119.2121.8 C.(corn), after two recrystallizations from n-heptane.

Analysis.Calcd. for C H ClN O: Cl, 8.46; N, 16.67. Found: Cl, 8.17; N,16.93.

N (2 dimethylaminoethyl)-7-chloro-4-(2-dimethylaminoethylamino) 3quinolinecarboxamide was prepared following the procedure described inExample 1 using 8.5 g. of ethyl 4,7-dichloro-3-quinolinecarboxylate, 5.4g. of Z-dimethylaminoethylamine, 8.5 g. of phenol and a heating periodof twenty hours at 130 C. There was thus obtained 2.0 g. ofN-(2-dimethylaminoethyl) -7- chloro-4-(2 dirnet-hylaminoethylamino) 3quinolinecarboxamide, M.P. 157.0-l58.4 C. (corr.), after tworecrystallizations, once from benzene-n-hexane and once from benzene.

Analysis.Calcd. for C H ClN O: Cl, 9.76; N, 19.21. Found: Cl, 9.75; N,19.09.

EXAMPLE 5 N (2 dimethylaminoethyl) 4 (2dimethylaminoethylamino)-3quinolinecarboxamide was prepared followingthe procedure described in Example 1 using 10.0 g. of ethyl4-chloro-3-quinolinecarboxylate, 7.4 g. of 2- dimethylaminoethylamine,10.0 g. of phenol and a heating period of twenty hours at 130 C. Therewas thus obtained 2.7 g. of N-(2-dimethylaminoethyl)-4(2-d-imethylaminoethylarnino)-3-quinolinecarboxamide, M.P. 128.8-129.6 C. (corr.), after recrystallization from benzene.

Analysis.Calcd. for C H N O: C, 65.63; H, 8.19; N, 21.26. Found: C,65.72; H, 8.25; N, 21.04.

EXAMPLE 6 Quaternary ammonium salt derivatives of my compounds ofFormula I are prepared by conventional means, as illustrated below.

(A) N-(Z-diethylaminoethyl) 4 (2diethylaminoethylamino)-3-quinolinecarboxylate tris methiodide-A mixturecontaining 6.3 g. of N(2-diethylaminoethyl)-4-(Z-diethylaminoethylamino) 3 quinolinecarboxamide, 14.2 g. of methyliodide and 50 m1. of anhydrous ethanol was allowed to stand at roomtemperature for about ten days whereupon an oil separated. The solventwas decanted, the oil dissolved in hot methanol, and the hot solutionallowed to cool. The resulting precipitate was collected to yield 9 g.of N-(2-diethylaminoethyl)-4-(2- diethylaminoethylamino) 3quinolinecarboxamide trismethiodide, M.P. 222.8-224.8 C. (corn), withdecomposition.

Analysis.Calcd. for C H I N O: I", 46.96; N, 8.64. Found: 1, 46.90; N,8.50.

Following the procedure described above in Example 6A but usingmolecular equivalent quantities of allyl bromide or benzyl chloride inplace of methyl iodide, the corresponding tris-allobromide ortris-benzochloride, respectively, is obtained.

EXAMPLE 7 'The preparation of the intermediate lower-alkyl 4-halo- 3( or2)-quinolinecarboxylates is illustrated in the following paragraphs:

(A) Ethyl 4 chloro 3 quinolinecarboxylate-A mixture containing 76 g. ofethyl 4-hydroxy-3-quinolinecarboxylate, 25 ml. of phosphorus oxychlorideand 500 ml. of ethylene dichloride was heated on a steam bath for aboutfive minutes to form a solution which was then refluxed with stirringfor an additional thirty minutes. Dilute (6 N) aqueous ammoniumhydroxide solution was added slowly with vigorous stirring at a rate tomaintain reflux until the solution was slightly basic. The mixture wasfiltered and the ethylene dichloride layer was separated, washedsuccessively with 1% aqueous sodium hydroxide solution and water, driedover anhydrous potas sium carbonate, and evaporated to yield an oilyresidue that solidified on cooling. This solid was recrystallized fromn-pentane to yield ethyl 4-chloro-3-quinolinecarpoxylate, M.P. 45.547.0C.

, Analysis.Calcd. for C H CINO Cl, 15 .04. Found: Cl, 15.04.

(B) Ethyl 4,7 dichloro-3-quinolinecarboxylate, M.P. 81-82" C., wasprepared following the procedure described in Example 7A using 21.0 g.of ethyl 7-chloro-4- hydroxy-3-quinolinecarboxylate, 7.6 ml. ofphosphorous oxychloride, 200 ml. of ethylene dichloride, a refluxingperiod of two hours, and a recrystallizing medium of ethylenedichloride-n-pentane.

Analysis.-Calcd. for C H Cl NO N, 5.17. Found: N, 5.10.

(C) Ethyl 4,7 dichloro 2 quinolinecarboxylate, M.P. -81 C., was preparedfollowing the procedure described in Example 7A using 84 g. of ethyl7-chloro-4- hydroxy-2-quinolinecarboxylate, 30 ml. of phosphorusoxychloride, 400 ml. of ethylene dichloride, and a refluxing period ofone hour.

(D) Ethyl 7 chloro 4 iodio 3 quinolinecarboxylate-To a refluxingsolution containing 25.5 g. of sodium iodide in 250 ml. of acetone wasadded 23.4 g. of ethyl 4,7 dichloro 3 quinolinecarboxylate followed by40 g. of ethyl iodide, and refluxing was continued for six hours. Thereaction mixture was allowed to cool and then stand at room temperature.The solid that separated was filtered oif. The filtrate was evaporatedto about one-third of its volume, treated with decolorizing charcoal,filtered and the filtrate cooled. The solid that separated wascollected, triturated well with water, filtered and dried in a vacuumoven at 70 C. for four hours to yield 19 g. of ethyl 7-chloro-4-iodo-3-quinolinecarboxylate, M.P. 113 C.

Analysis.-Calcd. for C H ClINO I, 35.12; 0, 8.85. Found: I, 35.34; 0,8.90.

(E) Ethyl 4-chloro 7 nitroquinoline 3 carboxylate-A mixture containing43.5 g. of ethyl 4-hydroxy-7- nitro-3-quinolinecarboxylate and 250 ml.of phosphorus oxychloride was refluxed for five hours and then most ofthe excess phosphorus oxychloride was distilled off in vacuo. Theconcentrate was poured with stirring into a mixture containing aboutequal parts of an excess of 7 concentrated ammonium hydroxide and wateralong with ice. The solid that separated was collected andrecrystallized twice from acetone to yield 5.5 g. of ethyl 4-chloro-7-nitroquinoline-3-carboxylate, M.P. 164.6-167.2 C. (corn).

Analysis.Calcd. for C1zI'I9C1N204: Cl, 12.63 N, 9.98. Found: Cl, 12.39;N, 9.99.

Following the procedure described in Example 7A using molar equivalentquantities of the appropriate loweralkyl 4-hydroxy-3(or2)-quinolinecarboxylate and phosphorus oxychloride, the followinglower-alkyl 4-chloro-3 (or 2)-quinolinecarboxylates are prepared.

(F) Ethyl 4,5-dichloro-3-quinolinecarboxylate, using ethyl-chloro-4-hydroxy-3-quinolinecarboxylate.

(G) Isopropyl 4,7 dichloro-3-quinolinecarboxylate, using isopropyl7-chloro 4 hydroxy 3 quinolinecarboxylate.

(H) Ethyl 4-chloro-8-ethoxy-3-quinolinecarboxylate, using ethyl8-ethoxy-4-hydroxy-3-quinolinecarboxylate.

(1). Methyl 4-chloro-7-methyl-3-quinolinecarboxylate,. using methyl4-hydroxy-7-methyl-3-quinolinecarboxylate.

(J) n-Propyl 4-chloro-2-quinolinecarboxylate, using n-propyl4-hydroxy-2-quinolinecarboxylate.

(K) Ethyl 4-chloro-6,7-dimethoxy 3 -'quinolinecarboxylate, using ethyl6,7-dimethoxy-4-hydroxy-3-quino linecarboxylate.

(L) n-Butyl 4-chloro-6-methoxy-3-quinolinecarboxylate, using n-butyl4-hydroxy-6-methoxy-3-quinolinecarboxylate.

(M) Methyl 4,7-dichloro 3 quinolinecarboxylate, using methyl7-chloro-4-hydroxy-3-quinolinecarboxylate.

(N) Isobutyl 4,7-dichloro 3 quinolinecarboxylate, using isobutyl7-chloro-4-hydroxy-3-quinolinecarboxylate.

(O) n-Hexyl 4,7-dichloro 2 quinolinecarboxylate, using n-hexyl7-chloro-4-hydroxy-2-quinolinecarboxylate.

EXAMPLE 8 Ethyl7-chloro-4-(Z-diethylaminoethylamino)-3-quinolinecarboxylateA mixturecontaining 7.2 g. of ethyl 7-chloro-4-iodo-3-quinolinecarboxylate, 4.6g. of 2-diethylaminoethylamine and'50 ml. of ethanol was heated on asteam bath for about fifteen minutes until a solution resulted. Thesolution was then allowed to cool and stand at room temperatureovernight. The solution was evaporated to dryness; the resulting solidwas triturated in about 2% aqueous potassium hydroxide solution,filtered and recrystallized from cyclohexane to yield 5 g. of ethyl 7chloro-4 -(Z-diethylaminoethylamino) 3 quinolinecarboxylate. The productwas converted into its dihydrochloride salt by .dissolving it in hotisopropyl alcohol, adding 8 ml. of 6 N ethanolic hydrogen chloride,filtering the hot solution, and allowing the filtrate to cool to roomtemperature. The precipitate was collected, .washed with acetone andrecrystallized from isopropyl alcohol to yield 4.0 gof ethyl7-chloro-4-(2-diethylaminoethylamino) 3 quinolinecarboxylatedihydrochloride, M.P. 188.8190.4 .C. (corn), with decomposition.

Analysis.-Calcd. for C H C1N O -2HCl: Cl, 25.16; N, 9.94. Found: Cl,24.85; N, 9.63.

EXAMPLE 9 and dilute hydrochloric acid, and the resulting solutionextracted with chloroform to remove the phenol. It was then made.neutraLwith 35% aqueous sodium hydroxide solution and extracted withchloroform to remove any unreacted ethyl4,7-dichloro-3-quinolinecarboxylate, and then made strongly basic with35 aqueous sodium hydroxide solution and extracted with chloroform. Thelast chloroform extract was dried over anhydrous potassium carbonate andevaporated to yield 2.4 g. of oil. The first two chloroform extractswere combined, extracted with 0.1 N hydrochloric acid, the acidicextract made alkaline with 35% aqueous sodium hydroxide solution, andthe alkaline solution extracted with chloroform. The chloroform extractwas dried and evaporated to yield 10.7 g. of

oil which was combined with the above 2.4 g. of oil. The combined oilwas dissolved in hot n-heptane, the hot solution treated withdecolorizing charcoal and filtered, and the filtrate cooled to yield asolid material. This solid was collected and recrystallized successivelyfrom n-heptane, n-hexane and acetonitrile, each time using decolorizingcharcoal. There was thus obtained 3.5 g. of ethyl 7-chloro-4-(Z-diethylaminoethylamino) 3 quinolinecarboxylate, M.P.97.0100.6 c.

Analysis.Ca1cd. for C H ClN O Cl, 10.13; N, 12.01. Found: Cl, 10.17; N,11.74.

EXAMPLE 10 Ethyl 4 (Z-diethylaminoethylamino)-3-quinolinecarboxylateAmixture containing 10.0 g. of ethyl 4-chloro- 3-quinolinecarboxylate,4.9 g. of Z-diethylaminoethylamine and 10.0 g. of phenol was heated at100 C. for twenty hours with stirring. The reaction mixture was pouredinto dilute hydrochloric acid. The acidic solution was extracted withchloroform, made strongly basic with 35% aqueous sodium hydroxidesolution, and the alkaline solution extracted with chloroform. Thesecond chloroform extract was washed with Water, dried over anhydrouspotassium carbonate and evaporated to yield an oil which solidified. Thesolid was recrystallized once from n-hexane and once from n-pentane toyield 2.7 g. of ethyl4-(Z-diethylaminoethylamino)-3-quinolinecarboxylate, M.P. 72.072.8 C.(corn).

Analysis.Calcd. for C18H25N302I C, H, N, 13.32. Found: C, 68.71; H,8.18; N, 13.26.

EXAMPLE 11 EXAMPLE 12 Ethyl 7-chloro-4-(S-diethylarnino 2pentylamino)-3- quinolinecarboxylateA slurry containing 27.0 g. of ethyl4,7-dichloro-3-quinolinecarboxylate and 39.5 g. of5-diethylamino-Z-pentylamine was stirred until an exothermic reactionresulted whereupon the temperature rose to about C. The reaction mixturewas allowed to stand over- 7 night at room temperature, and then treatedwith 300 ml. of water and 25 ml. of 35 aqueous sodium hydroxidesolution. The alkaline solution was extracted with chloroform; thechloroform extract was washed with water, dried over anhydrous potassiumcarbonate, and then evaporated under reduced pressure. The excess5-diethylamino-2-pentylamine was removed by warming the mixture in arotating evaporator at 0.2 mm; The residue was dissolved in 700 ml. ofabsolute ethanol, the ethanol solution warmed on a steam bath, and 168ml. of 1 M phosphoric acid in absolute ethanol was added with stirring.Sufiicient water was added tomake the solution almost clear and it was 7then allowed to cool overnight with stirring. The precipitate wascollected, washed with absolute ethanol and dried at 55 C. and 25 mm. toyield 37.8 g. of ethyl 7-chloro- 4-(5-diethylamino 2pentylamino)-3-quinolinecarboxylate as is diph-osphate. 20 g. of thisproduct was recrystallized using 40 ml. of hot water and 600 m1. of hotabsolute ethanol. The recrystallized product was collected and found tomelt at 190.4-191.0 C. (corn), with decomposition.

Analysis.-Calcd. for C21H3QC1N3O2.2H3P04: N, Cl, 6.03. Found: N, 7.17;Cl, 6.20.

EXAMPLE l3 Ethyl 7 chloro-4-(3-dimethylaminopropylamino) 3-quinolinecarboxylate as its diphosphate was obtained following theprocedure described in Example 12 using 27.0 g. of ethyl4,7-dichloro-3-quinolinecarboxylate and 25.3 g. of3-dimethylaminopropylamine. There was thus obtained 45.3 g. of theproduct, M.P. 2l7.0217.8 C. (corr.), with decomposition.

Analysis.Calcd. for C17H2 ClN3.2H3PO4I Cl, 6.66; N, 7.90. Found: Cl,6.76; N, 7.73.

EXAMPLE 14 Ethyl 7-chloro-4-(3-diethylamino 2hydroxypropylamino)-3-quinolinecarhoxylate was prepared following theprocedure described in Example 12 using 27.0 g. of ethyl4,7-dichloro-3-quinolinecarboxylate and 36.5 g. of3-diethylarnino-2-hydroxypropylamine. The product was recrystallizedonce from isopropyl alcohol-acetonitrile and then purified further byplacing it in a Soxhlet extractor and continuously extracting it withn-hexane. The first extract obtained after two hours and the secondextract obtained after two additional hours were combined and evaporatedin vacuo to yield 16.8 g. of the product, ethyl7-chloro-4-(3-diethylamino 2 hydroXypropylamino)-3-quinolinecarboxylate, M.P. ll5.2-1l6.8 C. (corn).

Analysis.Calcd. for C H ClN O Cl, 9.33; N, 11.06. Found: Cl, 9.37;N,11.34.

Ethyl 7-chloro-4-(3-diethylamino 2hydroxypropylamino)-3-quinolinecarboxylate was converted into itsdiphosphate acid-addition salt as follows: To a solution containing 57g. of ethyl7-chloro-4-(3-diethylamino-2-hydroxypropylamino)-3-quinolinecarboxylatein 650 ml. of ethanol at 50 C. was added dropwise, with stirring over aperiod of twenty minutes, a solution containing 34.5 g. of 85%phosphoric acid dissolved in a mixture of 100 ml. of ethanol and 10 ml.of water, whereupon a crystalline precipitate resulted. The mixture washeated at reflux for fifteen minutes and cooled in an ice bath. Theprecipitate was collected, Washed successively with 100 ml. of ethanoland 100 ml. of n-hexane, and dried at 65 in vacuo for three hours toyield 86 g. of ethyl7-chloro-4-(3-diethylamino-Z-hydroxypropylamino)-3-quinolinecarboxylatediphosphate, M.P. 217.0-2l8.0 C. (corn) with decomposition.

Analyis.Calcd. for C H ClN O 2H PO Base, 65.97%; N, 7.30; P, 10.77.Found: Base, 66%; N, 7.15; P, 11.02.

A 2 g. portion of the diphosphate was converted to l g. of the base,M.P. l13115 C.

Following the procedure described in Example 1 using corresponding molarequivalent quantities of the respective reactants and phenol, thecompounds of Examples 1527 are prepared.

EXAMPLE 15 N-(Z-piperidinoethyl) 7chloro-4-(2-piperidinoethylamino)-3-quinolinecarboxamide, using ethyl4,7-dichloro- 3-quinolinecarboxylate and Z-piperidinoethylamine.

EXAMPLE 16 N-(Z-pyrrolidinoethyl) 5chloro-4-(2-pyrrolidinoethylamino)-3-quinolinecarboxamide, using ethyl4,5-dichloro-3-quinolinecarboxylate and 2 pyrrolidinoethylamine.

10 EXAMPLE 17 N-(2-morpholinoethyl) 6 methoxy-4-(2-morpholinoethylamino)3 quinolinecarboxamide, using ethyl 4- chloro-6-methoxy 3quinolinecarboxylate and Z-morpholinoethylamine.

EXAMPLE 18 N-[2-(4-ethylpiperidino)ethyl] 7 bromo-4-[2-(-4-ethylpiperidino)ethylamino] 2 quinolinecarboxamide, using ethyl7-bromo-4-chloro-Z-quinolinecarboxylate and 2- (4-ethylpiperidinoethylamine.

EXAMPLE 19 N [2 (2,5 dimethylpyrrolidino)ethyl]-6,7-dimethoxy 4 [2 (2,5dimethylpyrrolidino)ethylamino]- 3-quinolinecarboxamide, using ethyl4-chloro-6,7-dimethoxy 3 quinolinecarboxylate and2-(2,5-dimethy1pyrrolidino) -ethyl amine.

EXAMPLE 20 N [2 (N' ethyl-N-2-hydroxyethylamino)ethyl]-4- [2 (Nethyl-N-2-hydroxyethylamino)ethylamino]-7-methyl-3-quinolinecarboxamide, using ethyl 4-chloro-7- methyl 3quinolinecarboxylate and 2-(N-ethyl-N-2-hydroxyethylamino)-ethylamine.

EXAMPLE 21 N-[5-(N-ethyl-N'-2-hydroxyethylamino) 2 pentyl]- 4-[5-(Nethyl-N'-2-hydroxyethylamino) 2 pentylamino]-3-quinolinecarboxamide,using ethyl 4-chlor0-3- quinolinecarboxylate and5-(N-ethyl-N-2-hydroxyethylamino) -2-pentylamine.

EXAMPLE 22 N- (Z-di-n-butylaminoethyl) -4-(2-di-n-butylaminoethylamino)-3-quinolinecarboxaxmide, using ethyl4-chloro-3- quinolinecarboxylate and 2-di-n butylaminoethylamine.

EXAMPLE 23N-(Z-di-n-hexylaminoethyl)-4-(2-di-n-hexylaminoethylamino)-7-trifluoromethyl-2-quinolinecarboxamide,using ethyl 4 -'chloro 7 trifluoromethyl 2 quinolinecarboxylate and2-n-hexylaminoethylamine.

EXAMPLE 24 N (6-dimethylaminohexyl) 7 chloro 4(6-dimethylarninohexylamino) 3 quinolinecarboxarnide, using ethyl4,7-dichloro-3quinolinecarboxylate and 6-dimethylaminohexylamine.

EXAMPLE 25 N [2 (2 diethylaminoethylmercapto)ethyl] 7- chloro 4 [2 (2diethylaminoethylmercapto)ethylamino] -3-quinolinecarboxamide, usingethyl 4,7-dichlor0- S-qninolinccarboxylate and2-(2-diethylaminoethylmercapto)ethylamine.

' EXAMPLE 26 N [3 (2 dimethylaminoethoxy)propyl] 4 [3 (2-dimethylaminoethoxy)propylamino] 3 quinolinecarboxamide, using ethyl4-chloro-3-quinolinecarboxylate and3-(Z-dimethylaminoethoxy)propylamine.

EXAMPLE 27 N (2 diethylaminoethyl) 4 (2diethylaminoethylamino)-7-nit.ro-3-quinolinecarboxamide, using ethyl 4-chloro-7-nitro-3-quinolinecarboxylate and 2- diethylaminoethylamine.

Following the procedure described in Example 12 using correspondingmolar equivalent quantities of the respective reactants, the compoundsof Examples 28-39 are prepared.

EXAMPLE 28 Ethyl5-chloro-4-(2-piperidinoethylamino)-3-quinolinecar-boxylate, using ethyl4,5-dichloro-3quinolinecarboxylate and 2-piperidinoethylamine.

1 1 EXAMPLE 29 Isopropyl7-chloro-4-(2-pyrrolidinoethylamino)-3-quinolinecarboxylate, usingisopropyl 4,7-dichloro-3-quinolinecanboxylate and2-pyrrolidinoethylamine.

EXAMPLE 3O Ethyl 8ethxy-4-(2-morpholinoethylamino)-3-quinolinecarboxylate, using ethyl4-chloro-8-ethoxy-3-quinolinecarboxylate and 2-morpholinoethylamine.

EXAMPLE 31 Methyl 4 [2-4-ethylpiperidino)ethylamino] 7methyl-3-quinolinecarboxylate, using methyl4-chlor0-7-methyl-3-quinolinecarboxylate and2-(4-ethylpiperidino)-ethylamine.

EXAMPLE 32 Ethyl 7chloro-4-[3-(Z-dimethylaminoethoxy)propylamino]-3-quinolinecarboxylate,using ethyl 4,7-dichloro- S-quinolinecarboxylate and3-(2-dimethylaminoethoxy) propylamine.

EXAMPLE 38 Ethyl 4 [2 (2 diethylaminoethylmercapto)ethylamino]-3-quinolinecarboxylate, using ethyl 4-chloro-3- quinolinecarboxylateand 2 (2 diethylaminoethylmercapto)ethylamine.

EXAMPLE 39 Ethyl 4 (2 diethylaminoethylamino) 7 nitro 3-quinolinecarboxylate, using ethyl 4-chloro-7-nitro-3-quino-'linecarboxylate and 2-diethylaminoethylamine.

Following the procedure described in Example 1 using equimolarquantities of the appropriate lower-alkyl 4-(tertiary-aminoalkylamino)-3-quinolinecarboxylate (Formula IV) and(lower-tertiary-amino)-lower-all ylamine (Formula Illa), the compoundsof Examples 40-47 are prepared. 7

EXAMPLE 4O 4 (2 diethylaminoethylamino) 7 chloro N (2-piperidinoethyl)-3-quinolinecarboxamide, using ethyl 7- chloro-4-(Z-diethylaminoethylamino) -3-quinolinecarb0xylate and2-piperidinoethylamine.

EXAMPLE 41 4 (2 diethylaminoethylamino) N [2-N-ethyl-N'- 2-hydr0xyethylamino ethyl] -3-quinolinecarboxamide, using ethyl4-(Z-diethylaminoethylamino)-3-quinoline-car- 12 boxylate and2-(N-ethyl-N-Z-hydroxyethylamino)ethylamine.

EXAMPLE .42

4 (3 diethylaminopropylamino) N (2dimethylaminoethyl)-3-quinolinecarboxamide, using ethyl 4-(3-diethylaminopropylamino)-3-quin0linecarboxylate and 2-dimethylaminoethylamine.

EXAMPLE 43 7-chloro-N-(Z-diethylaminoethyl) 4-(5-diethylamin0-Z-pentylamino)-3-quinolinecarboxamide, using ethyl 7- chloro 4(S-diethylamino-Z-pentylamino)-3-quinolinecarboxylate andZ-diethylaminoethylamine.

EXAMPLE 44 p 7 chloro 4-(3-dimethylaminopropylamino)-N-(2-pyrrolidinoethyl)-3-quinolinecarboxamide, using ethyl 7- chloro 4(3-dimethylaminopropylamino)-3-quinolinecarboxylate and2-pyrrolidinoethylamine.

EXAMPLE 45 7 chloro 4-(3-diethylamino-2-hydroxypropylamino)- N(6-dimethylaminohexyl) 3-quinolinecarboxarnide, using ethyl7-ch1or0-4-(3-diethylamino-2-hydroxypropylamino 3-quinolinecarboxylateand 6 dimethylaminohexylamine.

' EXAMPLE 46 5 chloro N-(3-diethylamino-2-hydroxypropyl)-4-(Z-piperidinoethylamino) 3-quinolinecarboxamide, using ethyl5-chl0ro-4-(2-piperidin0ethylamino) -3-q-uinolinecarboxylate and3-diethylamino-2-hydroxypropylamine.

EXAMPLE 47 7 chloro 4 (2 diethylaminoethylamino)-N-(3-dimethylaminopropyl) 2 quinolinecarboxamide, using ethyl7-chloro-4-(2-diethylaminoethylamino)-'3-quino1inecarboxylate and3-dimethylaminopropylamine.

EXAMPLE 4s n-Propyl 4-[2-(2,5-dimethylpyrrolidino)ethyl-amino]-2-quinolinecarboxylate is prepared following the procedure described inExample 10 using corresponding molar equivalent quantities of n-propyl4-chl'or o-2-quinolinecar-.

boxylate and 2-(2,5-dimethylpyrrolidino)ethylamine.

EXAMPLE 49 n-Hexyl 7 chloro- 4- (Z-diethylaminoethylamino)-2-quinolinecarboxylate is prepared following the procedure described inExample 10 using corresponding molar equivalent quantities of n-hexyl4,7-dichloro-2-quinolinecarboxylate and Z-diethylaminoethylamine.

EXAMPLE 50 Ethyl 7chloro-4-(Z-diethylaminoethylamino)-2-quinolinecarboxylate is preparedfollowing the procedure described in Example 10 using correspondingmolar equivalent quantities of ethyl 4,7-dichloro-2-quinolinecarboxylateand Z-diethylaminoethylamine.

EXAMPLE 51 Ethyl 7 chloro 4-(3-diethylaminopropylamino)-3-quinolinecarboxylate-To 54 g. of ethyl 4,7-dichl0ro-3-quinolinecarboxylate was added 65 g. of 3-diethylaminopropylamine andthe resulting mixture was stirred overnight at room temperature. Thereaction mixture was taken up in about'SOO ml. of n-hexane and 200 ml.of 10% aqueous sodium hydroxide solution. A creamy white precipitatesettled out in the hexane phase. The two phases were separated and theaqueous phase was extracted twice with ml. portions of n-hexane. Thehexane extracts were combined with the hexane phase and the resultingmixture was filtered to remove some White crystalline product Which wasair-dried to yield 435 g, of ethyl 7- chloro 4 (3diethylaminopropylamino)-3-quinolinecarboxylate, M.P. 63.565.0 C. Thehexane filtrate yielded more crystalline precipitate on standing; tothis mixture was added sufficient ether to dissolve the precipitate andthe resulting solution was washed with three 100 ml. portions of water,dried over anhydrous sodium sulfate, and then cooled to yield more ofthe white crystalline product. This additional portion of the productwas washed with cold n-hexane and dried overnight in vacuo at 45 C. toyield 37.1 g. of ethyl 7-chloro-4-(3- diethylaminopropylamino)3-quinolinecarboxylate, M.P. 71.8-73.6 C .(corr.).

Analysis.Calcd. for C19H2C1N302I Cl, N, 11.95, Found: Cl, 9.79; N,11.44.

EXAMPLE 52 Ethyl 7 chloro 4 (2 morpholinoethylamino)-3-quinolinecarboxylateTo 27.0 g. of ethyl 4,7-dichloro-3-quinolinecarboxylate was added 32.5 g. of 2-morpholinoethylamine;considerable heat evolved and a precipitate began to separate before theaddition of the morpholinoethylamine had been completed. After allowingthe reaction mixture to stand overnight at room temperature, theprecipitate was collected, taken up in about 250 ml. of hot chloroformand about 100 ml. of 10% aqueous sodium hydroxide solution, and shakenwell. The two phases were separated and the alkaline aqueous phase wasextracted with 100 ml. of chloroform; this chloroform extract wascombined with the chloroform phase. The resulting chloroform solutionwas washed twice with about 100 ml. of water, dried over anhydroussodium sulfate and evaporated by heating in vacuo on a steam bath toyield a solid which was recrystallized from benzene to yield 29.8 g. ofthe product, ethyl 7-chloro-4-(2-morpholinoethylamino) 3quinolinecarboxylate, M.P 151.0- 154.0 C. (corr.).

Anaylsis.Calcd. for CmHgzClNgOgI 11.56. Found: Cl, 10.00; N, 11.64,

EXAMPLE 5 3 Ethyl 7-benzyloxy-4-(5-diethylamino-2-penty1amino)-3-quinolinecarboxylate-A mixture containing 23.9 g. of ethyl7-benzyloxy-4-chloro-3 quinolinecarboxylate and 27.8 g. of5-diethylamino-2-pentylamine was stirred and then allowed to stand forthree days. The reaction mixture was then stirred on a steam bath forabout two hours, cooled and taken up with a mixture of 250 ml. ofchloroform and 100 ml. of 10% aqueous sodium hydroxide solution. Themixture was shaken well and the layers separated. The aqueous layer waswashed with about 100 ml. of chloroform and the chloroform washing wasadded to the original chloroform layer. The combined chloroform solutionwas washed successively with 100 ml. of 10% aqueous sodium bicarbonatesolution and twice with 100 ml. portions of water. The chloroformsolution was then dried over anhydrous sodium sulfate, filtered and thefiltrate concentrated in vacuo on a steam bath to yield a dark liquid.The liquid was distilled in vacuo to remove the excess startingalkylenediamine and the remaining oil was taken up in 50 ml. of hotabsolute ethanol. The hot ethanol solution Was added to 68 ml. of hotethanolic 1 M phosphoric acid solution, whereupon a red gummy materialseparated. A small quantity of methanol plus ml. of water and moreabsolute ethanol was added and the resulting mixture was triturated onthe steam bath for about ten minutes and then allowed to cool and standat room temperature overnight. The resulting crystalline precipitate wascollected, washed with absolute ethanol and dried in vacuo at 55 C.overnight to yield 21.1 g. of ethyl 7-benzyloxy4-(S-diethylamino-2-pentylamino)-3- quinolinecarboxylate diphosphate. A5.0 g. sample was recrystallized by dissolving it in 30 ml. of hotwater, adding decolorizing charcoal, filtering the mixture throughinfusorial earth (Super-Cel), adding 300 ml. of hot absolute ethanol tothe hot filtrate and allowing the mixture to cool. The white crystallineproduct was collected,

Cl, 9.75; N,

washed with small portions of the mother liquor and dried in vacuo at 55C. overnight to yield 3.4 g. of said diphosphate, M.P. 161.5-1635" C.

Anwlysis.Calcd for C21H31H3032H3PO4I N, P, 9.39. Found: N, 6.55; P,9.79.

The above intermediate ethyl 7-benzyloxy-4-chloro-3-quinolinecarboxylate was prepared in two steps as folliows: A mixturecontaining 138.2 g. of 3-benzyloxyaniline and 165.2 g. of diethylethoxymethylenemalonate was heated on a steam bath for one hour and thenallowed to cool to room temperature. The resulting crystalline diethylN-(B-benzyloxyanilino)-methylenemalonate was dissolved in 700 ml. ofDowtherm A (eutectic mixture of diphenyl and diphenyl ether) and thesolution heated with stirring to 250 C. and maintained at thistemperature for fifteen minutes, while distilling olf ethanol formed bythe reaction (51 ml. of ethanol collected). The reaction mixture wascooled and allowed to stand at room temper-ature overnight. Theresulting solid was collected by filtration, washed with n-hexane,tritu-rated in about 800 ml. of hot methanol, collected again byfiltration, and then dried in vacuo at 55 C. overnight to yield 75.1 g.of ethyl 7 benzyloxy-4-hydroxy-3-quinolinecarboxylate, M.P. 281 C. Amixture containing 25.0 g. of ethyl 7-benzyloxy-4-hydroxy-3-quinolinecarboxylate, 13.4 g. of phosphorusoxychloride and 220 ml. of ethylene dichloride was refluxed withstirring on a steam bath for two hours. The reaction mixture was thencooled and kept below 25 C. while adding dropwise to it 60 ml. of water.The phases were separated and allowed to stand at room temperatureovernight. To the ethylene dichloride phase containing a small quantityof separated solid was added 150 ml. of 35% aqueous sodium hydroxidesolution and the mixture shaken well. The ethylene dichloride phase wasseparated, washed twice with 250 ml. portions of water, dried overanhydrous sodium sulfate overnight and filtered through anhydrous sodiumsulfate. The filtrate was concentrated in vacuo on a steam bath to yield23.9 g. of crystalline ethyl 7-benzyloxy-4-chloro3-quinolinecarboxylate.

EXAMPLE 54 Ethyl 4- (S-diethylamino-2-pentylamino -7-hydroxy-3-quinolinecarboxylate was prepared by catalytic hydro genation of thecorresponding 7-benzyloxy compound or Example 53, as follows: A 6.6 g.portion of ethyl 7- benzyloxy-4-(5-diethylamino-2-pentylamino) 3qlllllulinecarboxylate diphosphate in 100 ml. of aqueous ethanol washydrogenated at atmospheric pressure (753 mm.) and room temperature (31C.) in the presence or 0.5 g. of 10% palladium-on-charcoal. Thetheoretical volume of hydrogen was taken up in forty minutes. Thecatalyst was filtered off and the filtrate evaporated to cloudiness andallowed to stand at room temperature whereupon the crystalline productseparated. Isopropyl alcohol was added to the mixture in small portionsuntil no further product separated. The solid product was collected,washed with isopropyl alcohol, dried overnight at 50 C. and 20 mm.,recrystallized from ethanol-water and dried for eighteen hours at 50 C.and 20 mm. to yield 4.8 g. of ethyl 4-(5-diethylamino-Z-pentylamino)-7-hydroxy-3-quinolinecarboxylate diphosphate, M.P. 203.0- 205.0 C. (corr.)with decomposition.

Analysis.Calcd. for C21H31N3032H3P04Z N, P, 10.88. Found: N, 7.56; P,10.95.

EXAMPLE 55 n Propyl 7 chloro 4 (5 diethylamino 2pentylamino)-3-quinolinecarboxylateA mixture containing 12.75 g. ofethyl 7-chloro-4-(S-diethylamino-Z-pentylamino)-3-quinolinecarboxylatein 50 ml. of benzene and a solution containing 0.5 g. of sodiumdissolved in n-propanel was refluxed on a steam bath for three days. Thereaction mixture was taken up in 500 ml. of benzene and washed twicewith 200 m1. portions of hot water, dried over anhydrous sodium sulfate,and filtered through anhydrous sodium sulfate. The filtrate wasconcentrated by heating it in vacuo to yield a dark liquid residue. Theliquid residue was taken up in 50 ml. of hot absolute ethanol and theresulting hot solution was added to 51 ml. of hot ethanolic 1 Mphosphoric acid solution to yield an amber oil. Small amounts ofmethanol and water were added whereupon some of the oil dissolved. Themixture was triturated while allowing to cool, whereupon a gummyprecipitate became crystalline. The crystalline product was collected,washed with small portions of the mother liquor and dried in vacuo at 55C. for three days. The product was recrystallized by dissolving it in 20ml. of hot water, filtering the solution, adding to the filtrate 600 m1.of absolute ethanol and 200 ml. of absolute ether, and cooling thesolution overnight. The resulting crystalline product was collected,washed with absolute ether and dried in vacuo at 55 C. overnight toyield 3.2 g. of n-propyl 7-chloro-4- -diethylamino-2-pentylamino-3-quinolinecarboxylate diphosphate, M.P. 154.5158.5 C.

Analysis.Calcd. for C H ClN O -2H PO N, 6.98; P, 10.29. Found: N, 6.91;P, 10.24.

EXAMPLE 5'6 Methyl 7 chloro 4 (5 diethylamino 2pentylamino)-3-quinolinecarboxylateA mixture containing 12.75 g. ofethyl 7-chloro-4-(5-diethylamino-2-pentylamino)-3-quinolinecarboxylatein 50 ml. of benzene and 1.0 g. of sodium methoxide in 100 ml. ofmethanol was refluxed on a steam bath for three days. The reactionmixture was taken up in 500 ml. of benzene and washed twice with 250 m1.portions of warm water, dried over anhydrous sodium sulfate and filteredthrough anhydrous sodium sulfate. The filtrate was concentrated byheating it in vacuo on a steam bath to yield a liquid which was taken upin 50 ml. of hot absolute ethanol. The hot solution was added to 66 ml.of hot 1 M ethanolic phosphoric acid solution. A yellow gum separated.Small amounts of methanol and water were added to the mixture which washeated on a steam bath whereupon partial dissolution of the gumresulted. The mixture was allowed to cool and the gummy material wastriturated. The resulting mixture was allowed to stand overnightwhereupon some crystals formed along with the gummy material. Themixture was triturated whereupon all of the gummy material becamecrystalline. The crystalline product was then collected, washed withsmall portions of the mother liquor and dried in vacuo at 55 C.overnight. The product was recrystallized by dissolving it in 25 ml. ofhot water, filtering the solution and adding to the filtrate 450 ml. ofabsolute ethanol to cloudiness and allowing the mixture to cool andstand overnight. The resulting crystalline product was collected, washedwith small portions of the mother liquor and dried in vacuo at 55 C.overnight to yield 13.8 g. of methyl 7-chloro-4-(5-diethylamino-2pentylamino)-3- quinolinecarboxylate diphosphate, M.P. 182-183 C.

Analysis.Calcd. for C2QHZ8CIN3O2'ZH3PO4Z N, P, 10.80. Found: N, 7.33; P,10.64.

EXAMPLE 57 Ethyl 4-(S-diethylamino-Z-pentylamino)-7-methoxy-3-quinolinecarboxylate-A mixture containing 18.3 g. of ethyl4-chloro-7-methoxy-3-quinolinecarboxylate and 27.4 g. of5-diethylamino-2-pentylarnine was stirred for five hours and then withcontinued stirring, was heated on a steam bath for one hour and cooled.The reaction mixture was taken up in 250 ml. of chloroform and thenextracted with 100 ml. of 10% aqueous sodium hydroxide solution.

The remaining chloroform solution was washed successively with 100 ml.of 10% aqueous sodium bicarbonate solution and twice with 150 ml.portions of water, dried over anhydrous sodium sulfate and filteredthrough anhydrous sodium sulfate. The filtrate was distilled in vacuo toremove the excess S-diethylamino-2-pentylamine. The remaining 25.3 g. ofresidue was taken up in 100 ml. of

hot absolute ethanol and added to 131 ml. of hot 1 M ethanolicphosphoric acid solution whereupon a gummy precipitate resulted. Smallamounts of methanol and water were added, and to the resulting stirredmixture at about 50 C. was added isopropyl alcohol until cloudinessresulted. The mixture was allowed to cool to room temperature and wasstirred overnight. The crystals which had formed were collected, washedwith small portions of the mother liquor, dried in vacuo at 55 C.overnight and then recrystallized by dissolving them in 50 ml. of hotwater, treating the solution with decolorizing charcoal, filtering themixture through infuson'al earth, and adding 300 ml. of isopropanol tothe filtrate. There separated a semi-crystalline oily material whichcrystallized completely when cooled and allowed to stand overnight.There was thus obtained 13.2 g. of ethyl 4-(5-diethylamino-2-pentylarnino)-7-methoxy-3-quinolinecarboxylate diphosphate, M.P. -1125C.

AHQIYSiSr-CfllCd. for C22H33N303'2H3PO41 N, P, 10.62. Found: N, 7.30; P,10.70.

EXAMPLE 5 8 Ethyl 7 chloro-4-[5-(Nethyl-N-Z-hydroxyethylamino)-2-pentylamino] 3-quinolinecarboxylate-54.0g. of ethyl 4,7-dichloro-3-quinolinecarboxylate and 87.0 g. of 5(N-ethyl-N-Z-hydroxyethylamino) 2 pentylamine were mixed with stirringwhereupon there was considerable evolution of heat. The resultingmixture was allowed to cool to room temperature and was stirred at thistemperature overnight. The reaction mixture was taken up in about 500ml. of chloroform and 200 ml. of 10% aqueous sodium hydroxide solution.The resulting mixture was shaken well and the chloroform phase wasseparated, washed with 100 ml. of water, dried over anhydrous sodiumsulfate and then concentrated in vacuo to remove the startingalkylenediamine and to yield in crude free base form the product, ethyl7-chloro-4-[5-(N-ethyl- N-Z-hydroxyethylamino) 2 pentylamino] 3quinolinecarboxylate. A portion of the base was converted into itsdihydrochloride salt as follows: 19.8 g. of said base was dissolved inml. of hot isopropyl alcohol and the solution treated with 10 ml. ofconcentrated hydrochloric acid. When no precipitate separated, thesolvent was removed by distilling in vacuo. The residue was trituratedwith isopropyl alcohol and ethyl acetate, and the mixture cooled at 3 C.for three days. The resulting semi-crystalline gummy material wasseparated and triturated with absolute ether, and the mixture cooled.The resulting crystalline product was collected, washed with smallportions of absolute ether and dried in vacuo at 55 C. overnight. Thisproduct was further purified by dissolving it in 70 ml. of hot absoluteethanol, treating the solution with decolorizing charcoal, filtering themixture through infusorial earth, cooling the filtrate, separating theresulting gummy material, triturating the gummy material with 340 ml. ofabsolute ether, cooling the mixture, separating the resultingcrystalline product, washing it with absolute ether and drying it invacuo at 55 C. overnight to yield 16.8 g. of ethyl 7-chloro-4-[5-(N-ethyl-N-2 hydroxyethylamino) 2 pentylamino]-3- quinolinecarboxylatedihydrochloride, M.P. 1-69.'0170.0' C. (corn) with decomposition.

' Analysis.Calcd. for C H ClN O -2HCl: Cl, 22.12; N, 8.74. Found: Cl,21.88; N, 8.70.

EXAMPLE 59 Ethyl 4 (5 diethylamino 2pentylamino)-3-quinolinecarboxylate47.14 g. of ethyl4-chloro-3-quinolinecarboxylate was mixed while stirring with 79.2 g. of5- diethylamino-Z-pentylamine whereupon an exothermic reaction resulted.The reaction mixture was stirred overnight and then taken up with amixture of 200 ml. of 10% aqueous sodium hydroxide solution and 500 ml.of n-hexane-benzene (4:1 ratio). The phases were separated and thealkaline phase was extracted twice with 100 ml.

portions of 4:1 n-hexane-benzene and the extracts were combined with then-hexane-benzene phase. The resulting n-hexane-benzene solution waswashed twenty times with 100 ml. portions of water, dried over anhydroussodium sulfate and heated on a steam bath in vacuo using a wateraspirator to yield 66.9 g. of the crude oily product in free base form.A 31.5 g. portion of the crude free base form was dissolved in 150 ml.of isopropyl alcohol and the solution treated with 18 ml. ofconcentrated hydrochloric acid. When no precipitate separated, thealcohol was removed by distilling in vacuo. The semi-crystalline productwas recrystallized once from absolute ethanol (175 ml.)-absolute ether(1600 ml.) and once from isopropyl alcohol (100 ml.)-absolute ether (375ml), using a decolorizing charcoal treatment on the hot isopropylalcohol solution, to yield 32.0 g. of ethyl 4-(5 diethylamino 2pentylamino) 3 quino linecarboxylate dihydrochloride, M.P. 176.0176.5 C.(corn) with decomposition, after drying in vacuo at 55 C. for threedays.

Analysis.-Calcd. for C21H31N302.2HC11 C, H, 7.73; Cl, 16.48; N, 9.76.Found: C, 58.59; H, 8.00; Cl, 16.54; N, 9.86.

I claim:

I. A compound of the formula where Y and Y are each lower-alkylenehaving from two to six carbon atoms and having its conecting linkages ondifferent carbon atoms, NB and NB are each tertiaryamino selected fromthe group consisting of di- (lower-alkyl)amino, N-(lower-alkyl) N(lower-hydroxyalkyhamino, piperidino, (lower-alkyl) piperidino,pyrrolidino, (lower-alkyl) pyrrolidino and morpholino.

2. A compound according to claim 1 in which --CONHYNB is attached at the3-position of the quinoline nucleus, and NB and NB are each N(loweralky1) 3. N-(2 diethylaminoethyl) 4 (2 diethylaminoethylamino) 3quinolinecarboxamide according to claim 2 in which Y and Y are each CHCH and loweralkyl in each instance is C 11 4. N (2 diethylaminoethyl) 7chloro 4 (2- diethylaminoethylamino) 3 quinolinecarboxamide according toclaim 2 in which Y and Y are each CH CH lower-alkyl in each instance isC H and the quinoline nucleus is substituted at its 7-position bychloro.

5. N (2 dimethylaminoethyl) 7 chloro 4 (2- dimethylaminoethylamino) 3quinolinecarboxamide according to claim 2 in which Y and Y are each CHCH lower-alkyl in each instance is CH and the quinoline nucleus issubstituted at its 7-position by chloro.

6. N-(Z-dimethylaminoethyl) 4 (2dimethylaminoethylamino)-3-quinolinecarboxamide according to claim 2 inwhich Y and Y are each CH CH and lower-alkyl in each instance is CH 7.N-(2-diethylaminoethyl) 7 chloro 4-(2-diethylaminoethylamino)-2-quinolinecarboxamide according to claim 1in which CONH--Y'NB' is attached at the 2-position of the quinolinenucleus, Y and Y are each CH CH NB and NB are each N(C H and thequinoline nucleus is substituted at its 7-position by chloro.

8. A compound of the formula C O O-(lower-alkyl) and Y is lower-alkylenehaving from two to six carbon atoms and having its connecting linkageson different carbon atoms and NB is tertiary-amino selected from thegroup consisting of di-(lower-alkyDarnino,N-(loweralkyl)-N-(lower-hydroxya1kyl)amino, piperidino,(loweralkyl)-piperidino, pyrrolidino, (lower-alkyl)-pyrrolidino andmorpholino.

9. A compound according to claim 8 in which COO-(loWer-alkyl) isattached at the 3-position of the quinoline nucleus and NB isN(lower-alkyl) 10. Ethyl4-(3-diethylaminopropylamino)-3-quin0linecarboxylate according to claim9 in which Y is CH CH CH and lower-alkyl in each instance is C H 11.Ethyl 4- (2-diethylaminoethylamino)-3-quinolinecarboxylate according toclaim 9 in which Y is CH CH and lower-alkyl in each instance is C H 12.Ethyl 7-chloro-4-(2 diethylaminoethylamino)-3- quinolinecarboxylateaccording to claim 9 in which Y is CH CH lower-alkyl in each instance isC H and the quinoline nucleus is substituted at its 7-position bychloro.

13. Ethyl 7-chloro-4-(5-diethylamino-2-pentylamino)-3-quinolinecarboxylate according to claim 8 in which YNB is CH(CH )CH CHCH N (C H -COOC H is attached at the 3-position of the quinolinenucleus, and the quinoline nucleus is substituted at its 7-position bychloro.

14. Ethyl 7-chloro-4-(3 dimethylaminopropylamino) 3-quinolinecarboxylateaccording to claim 9 in which YNB is CH CH CH N (CH lower-alkyl is C Hand the quinoline nucleus is substituted at its 7-position by chloro.

15. Ethyl7-chloro-4-(3-diethylamino-2-hydroxypropylamino)3-quinolinecarboxylateaccording to claim 9 in which YNB is CH CH(OH)CH TN(C H loweralkyl isethyl, and the quinoline nucleus is substituted at its 7-position bychloro.

16. Ethyl 7-chloro-4-(3 diethylaminopropylamino)-3- quinolinecarboxylateaccording to claim 9 in which YNB is CH CH CH N(C H lower-alkyl isethyl, and the quinoline nucleus is substituted at its 7-position bychloro.

17. Ethyl 7 chloro 4 (2-morpholinoethylarnino)-3- quinolinecarboxylateaccording to claim 8 in which Y is CH CH NB is morpholino, -COOC H isattached at the 3-position of the quinoline nucleus, and, the quinolinenucleus is substituted at its 7-position by chloro.

18. n-Propyl 7 chloro 4(S-diethylamino-Z-pentylamino)-3-quinolinecarboxylate according to claim8 in which YNB is CH(CH )CH CH CH N(C H COOCH CH CH is attached at the3-position of the quinoline nucleus, and the quinoline nucleus issubstituted at its 7-position by chloro.

19. Methyl 7-chloro-4-(S-diethylamino-2-pentylamino)3-quinolinecarboxylate according to claim 8 in which YNB is CH(CH )CH CHCH N(C H -COOCH is attached at the 3-position of the quinoline nucleus,and the quinoline nucleus is substituted at its 7-position by chloro.

20. Ethyl 7-chloro 4 [5-(N-ethyl-N-Z-hydroxyethylamino)-2-pentylamino]-3-quinolinecarboxylate according to claim 8 in which YNB is CH(CH CH CHCH N (C H (CH CH OH) OOOC H is attached at the 3-position of thequinoline nucleus, and the quinoline nucleus is substituted at its7-position by chloro.

21. Ethyl 4-(5-'diethylamino-2-pentylamino) -3-quinolinecarboxylateaccording to claim 8 in which Y--NB is and is attached at the 3-positionof the quinoline nucleus.

No references cited.

ALEX MAZEL, Primary Examiner.

I. TOVAR, Assistant Examiner.

UNITED STATES PATENT O FFICE CERTIFICATE OF CORRECTION Patent No.3,362,954 January 9, 1968 Alexander R. Surrey It is certified that errorappears in the above identified patent and that said Letters Patent arehereby corrected as shown below:

Column 2 line 24 "Y and Y are" should read Y=Y and line 25, "NB=NB"'should read NB NB Column 4, line 72, "3quinolinecarboxyamide should read3- quinolinecarboxamide Column 5, line 14, "tubidity" should readturbidity line 72, "-3-quinolinecarboxy1ate" should read-3-quinolinecarboxamide Column 6, lines 35 and 36,"-3-quinolinecarpoxylate" should read -3-quinolinecarboxylate Column 11,line 12, "[2-4-ethylpiperidino)ethylamino]" should read[2-(4ethy1piperidino]ethylamino] line 73, [2N-ethyl-N"' should read [2-(N -ethyl-N Column 14, line 4, "C H31H3O3" and "7.38" ShOLlld readC28H37N203 and 6.37 respectively. Column 17, line 34, "conecting" shouldread connecting Signed and sealed this 13th day of January 1970.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. WILLIAM E. SCHUYLER, JR. Attesting OfficerCommissioner of Patents

1. A COMPOUND OF THE FORMULA
 8. A COMPOUND OF THE FORMULA
 17. ETHYL 7 -CHLORO - 4 - (2-MORPHOLINOETHYLAMINO)-3QUINOLINECARBOXYLATE ACCORDING TOCLAIM 8 IN WHICH Y IS CH2CH2, NB IS MORPHOLINO, -COOC2H5 IS ATTACHED ATTHE 3-POSITION OF THE QUINOLINE NUCLEUS, AND, THE QUINOLINE NUCLEUS ISSUBSTITUTED AT ITS 7-POSITION BY CHLORO.